CN112315972B

CN112315972B - Composition for preparing intestinal tract

Info

Publication number: CN112315972B
Application number: CN202010955354.7A
Authority: CN
Inventors: 石国良; 林卫军; 王羽娟; 郭志坚; 蔡许彬
Original assignee: Thomson Biotech Xiamen Pte Ltd
Current assignee: Thomson Biotech Xiamen Pte Ltd
Priority date: 2020-09-11
Filing date: 2020-09-11
Publication date: 2022-03-18
Anticipated expiration: 2040-09-11
Also published as: CN112315972A

Abstract

The present invention relates to a composition for use in the preparation of the intestine. Specifically, the invention provides a composition, which comprises PEG and arabinose. The composition of the present invention has excellent bowel cleansing effect and patient compliance.

Description

Composition for preparing intestinal tract

Technical Field

The invention relates to the field of medicines, and in particular relates to a composition for intestinal tract preparation.

Background

With the development of endoscope technology, enteroscopy is widely used in clinic and becomes one of the main means for diagnosing and treating various intestinal diseases. Enteroscopy is affected to some extent by bowel preparation, and making adequate bowel preparation before surgery to improve colonoscopic image quality is extremely important to improve the detection rate of colonic disease.

Intestinal tract preparation refers to a method for removing feces from the intestinal tract, reducing the number of bacteria in the intestinal tract and postoperative complications by means of oral cathartic or enema. The intestinal tract preparation is widely used before intestinal tract operation, colonoscope, enteroscope, capsule endoscope diagnosis and treatment and imaging examination, and is the key to the success of the enteroscope examination and the intestinal tract operation. The ideal bowel preparation should have the following characteristics: the intestinal contents can be discharged in a short time; does not cause changes in the intestinal mucosa; does not cause the water electrolyte to be disordered; is economical and practical; the operation is simple. At present, the existing methods for preparing the intestinal tract in clinic are various, but the ideal cleaning effect is often difficult to achieve. The intestinal tract preparation methods are different, the effects are different, and the selection of the intestinal tract preparation method with good intestinal tract clearing effect, small side effect and wide application range is very important.

Polyethylene glycol (PEG) is a commonly used intestinal tract preparation medicine, PEG has the advantages of simple method, low price and the like, however, oral PEG has adverse reaction symptoms such as nausea, vomiting, abdominal distension and the like, in addition, PEG has unsatisfactory intestinal tract clearing effect and cannot achieve the effect of enteroscopy observation, so that a patient can repeat the intestinal tract preparation process, the psychology of intestinal tract preparation before enteroscopy of the patient is influenced, the compliance of the patient is greatly reduced, the preparation effect is not achieved far, and the medical burden of the enteroscopy can be increased.

Therefore, there is a need in the art to develop a bowel clearing drug with excellent bowel clearing effect and good patient compliance.

Disclosure of Invention

An object of the present invention is to provide a composition having an excellent bowel cleansing effect and good patient compliance.

Another object of the present invention is to provide the use of arabinose for the treatment of bowel movements, bowel preparation and for the amelioration of nausea, vomiting, abdominal pain, etc.

In a first aspect, the invention provides a composition comprising PEG and arabinose.

Preferably, the arabinose comprises L-arabinose.

The PEG is selected from the following group: PEG200, PEG400, PEG600, PEG1000, PEG2000, PEG4000, PEG6000, PEG8000, or combinations thereof.

Preferably, the weight ratio of the PEG to the arabinose is 0.5-20: 1, preferably 0.5 to 10: 1, more preferably 0.5-5:1, more preferably 1-3: 1.

Preferably, the PEG is present in an amount of 1 to 99 wt%, preferably 10 to 90 wt%, more preferably 20 to 80 wt%, based on the total weight of the composition.

Preferably, the arabinose is present in an amount of 1 to 99 wt%, preferably 10 to 90 wt%, more preferably 20 to 80 wt%, based on the total weight of the composition.

Preferably, the composition is a pharmaceutical composition, a food composition or a health care composition.

Preferably, the composition further comprises a pharmaceutically, food or nutraceutical acceptable carrier.

Preferably, the composition is in a solid or liquid form.

Preferably, the composition is in the form of oral preparation or injection preparation.

Preferably, the composition is in the form of emulsion, tablet, capsule, oral liquid, granule, powder or syrup.

Preferably, the composition is an emulsion comprising:

(A) an aqueous phase comprising arabinose, PEG and water;

(B) the oil phase comprises rapeseed oil, sunflower seed oil and olive oil; and

(C) and the emulsifier comprises sorbitan monooleate and glyceryl monostearate.

Preferably, the arabinose is 30 to 70 parts by weight, preferably 40 to 60 parts by weight, preferably 45 to 55 parts by weight.

Preferably, the weight part of the PEG is 50 to 150 parts, preferably 80 to 120 parts, and preferably 90 to 110 parts.

Preferably, the weight part of the water is 180-260 parts, preferably 200-240 parts, preferably 210-230 parts.

Preferably, the rapeseed oil is prepared from 240-320 parts by weight, preferably 260-300 parts by weight, and preferably 270-290 parts by weight.

Preferably, the weight part of the sunflower seed oil is 120-180 parts, preferably 130-170 parts, preferably 140-160 parts.

Preferably, the olive oil is present in an amount of 50 to 150 parts by weight, preferably 80 to 120 parts by weight, preferably 90 to 110 parts by weight.

Preferably, the sorbitan monooleate is used in an amount of 40 to 80 parts by weight, preferably 50 to 70 parts by weight, more preferably 55 to 65 parts by weight.

Preferably, the weight part of the glyceryl monostearate is 20-60 parts, preferably 30-50 parts, and preferably 35-45 parts.

Preferably, the unit of parts by weight is grams (g).

Preferably, the formulation of said emulsion comprises:

prescription components	Parts by weight
		Rapeseed oil	240-320
Sunflower seed oil	120-180
		Olive oil	50-150
Sorbitan monooleate	40-80
		Glyceryl monostearate	20-60
L-arabinose	30-70
		PEG	50-150
Water (W)	180-260

Preferably, the formulation of said emulsion comprises:

prescription components	Parts by weight
		Rapeseed oil	260-300
Sunflower seed oil	130-170
		Olive oil	80-120
Sorbitan monooleate	50-70
		Glyceryl monostearate	30-50
L-arabinose	40-60
		PEG	80-120
Water (W)	200-240

Preferably, the formulation of said emulsion comprises:

preferably, the emulsion is a water-in-oil emulsion.

Preferably, the particle size of the emulsion is 40-120nm, preferably 50-90nm, more preferably 65-80 nm.

Preferably, the emulsion is prepared by the following method:

(1) mixing the components of the water phase according to the prescription amount, heating to 65-80 ℃, and mixing to obtain a water-based phase A;

(2) mixing the oil phase components and the emulsifier components according to the prescription amount, heating to 65-80 ℃, and mixing to obtain an oily phase B;

(3) slowly injecting the aqueous phase A into the oily phase B under stirring, continuously and uniformly stirring for 4-8min, homogenizing for 5min under 10000-14000 r/min by a homogenizer, and fully emulsifying to obtain the emulsion.

In a second aspect the present invention provides the use of a composition according to the first aspect of the invention for the manufacture of a medicament for one or more uses selected from the group consisting of: (a) as a laxative; (b) for bowel preparation.

In a third aspect, the present invention provides the use of arabinose, for the preparation of a composition for one or more of the uses selected from the group consisting of: (i) as a laxative; (ii) for bowel preparation; (iii) prevention and/or treatment of nausea; (iv) preventing and/or treating emesis; (v) prevention and/or treatment of abdominal distension; and/or (vi) preventing and/or treating side effects of oral PEG.

Preferably, the PEG is selected from the group consisting of: PEG200, PEG400, PEG600, PEG1000, PEG2000, PEG4000, PEG6000, PEG8000, or combinations thereof.

Preferably, the arabinose comprises L-arabinose.

Preferably, the nausea comprises oral PEG-induced nausea.

Preferably, the emesis comprises oral PEG-induced emesis.

Preferably, said abdominal distension comprises abdominal distension induced by oral PEG.

Preferably, the side effects of PEG are selected from the group consisting of: nausea, vomiting, abdominal distension, or a combination thereof.

Preferably, the composition is in a solid or liquid form.

Preferably, the composition is in the form of tablets, capsules, oral liquid, granules, powder or syrup.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The invention finds that the arabinose and PEG combined medicine has synergistic effect on the effects of relaxing bowel, promoting excretion and preparing intestinal tracts. In addition, the arabinose can be used for relaxing bowel, promoting excretion and intestinal tract preparation, and can improve the side effects (such as nausea, vomit, abdominal distension and the like) of oral PEG. Therefore, the arabinose and PEG combined drug has the advantages of excellent bowel clearing effect and good patient compliance.

Term(s) for

As used herein, the terms "comprising," including, "and" containing "are used interchangeably and include not only open-ended definitions, but also semi-closed and closed-ended definitions, and include" consisting of … …, "" consisting essentially of … ….

As used herein, the terms "PEG" and "polyethylene glycol" are used interchangeably.

As used herein, sorbitan monooleate is also known as Span 80, Span-80.

The following description of the exemplary embodiments of the present application, including various details of the embodiments of the present application to assist in understanding, should be taken as exemplary only. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the present application. Also, descriptions of well-known functions and constructions are omitted in the following description for clarity and conciseness.

Composition comprising a metal oxide and a metal oxide

The invention provides a composition comprising PEG and arabinose.

In a preferred embodiment, the arabinose comprises L-arabinose.

In another preferred embodiment, the PEG is selected from the group consisting of: PEG200, PEG400, PEG600, PEG1000, PEG2000, PEG4000, PEG6000, PEG8000, or combinations thereof.

In another preferred mode, the weight ratio of the PEG to the arabinose is 0.5-20: 1, preferably 0.5 to 10: 1, more preferably 0.5-5:1, more preferably 1-3: 1.

The composition can be a pharmaceutical composition, a food composition or a health-care product composition.

The composition of the invention can also comprise a pharmaceutically, food or health product acceptable carrier. As used herein, the term "pharmaceutically, comestibly or nutraceutically acceptable carrier" refers to: one or more compatible solid, semi-solid, liquid or gel fillers suitable for human or animal use and of sufficient purity and sufficiently low toxicity. It is to be understood that, in the present invention, the carrier is not particularly limited and may be selected from materials commonly used in the art, or prepared by a conventional method, or commercially available. Examples of the pharmaceutically acceptable carrier moiety are cellulose and its derivatives (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, etc.), polyols (e.g., propylene glycol, glycerin, sorbitol, etc.), emulsifiers (e.g., tween), wetting agents (e.g., sodium laurylsulfate), buffers, chelating agents, thickeners, pH adjusters, transdermal enhancers, colorants, flavors, stabilizers, antioxidants, preservatives, bacteriostats, pyrogen-free water, etc.

In the present invention, the dosage form of the composition may be a solid preparation or a liquid preparation. Preferably, the composition is in the form of oral preparation or injection preparation. Typically, the composition is in the form of emulsion, tablet, capsule, oral liquid, granule, powder or syrup.

In a preferred embodiment of the present invention, the composition is an emulsion.

The present invention provides an emulsion comprising:

(A) an aqueous phase comprising arabinose, PEG and water;

(B) the oil phase comprises rapeseed oil, sunflower seed oil and olive oil; and

(C) and the emulsifier comprises sorbitan monooleate and glyceryl monostearate.

Preferably, the unit of parts by weight is grams (g).

Typically, the formulation of the emulsion comprises:

typically, the formulation of the emulsion comprises:

prescription components	Parts by weight
		Rapeseed oil	270-290
Sunflower seed oil	140-160
		Olive oil	90-110
Sorbitan monooleate	55-65
		Glyceryl monostearate	35-45
L-arabinose	45-55
		PEG	90-110
Water (W)	210-230

Preferably, the emulsion is a water-in-oil emulsion.

Preferably, the emulsion is prepared by the following method:

Use of

The present invention provides a composition of the invention for use (a) as a laxative; and/or (b) in aspects of gut preparation.

The invention also provides a use of arabinose in a method of use (i) as a laxative; (ii) for bowel preparation; (iii) prevention and/or treatment of nausea; (iv) preventing and/or treating emesis; (v) prevention and/or treatment of abdominal distension; and/or (vi) preventing and/or treating side effects of oral PEG.

Preferably, the nausea comprises oral PEG-induced nausea.

Preferably, the emesis comprises oral PEG-induced emesis.

The main technical effects obtained by the invention comprise:

1. the invention finds that the arabinose and PEG combined medicine has synergistic effect on the effects of relaxing bowel, promoting excretion and preparing intestinal tracts. The arabinose also finds that the arabinose can be used for relaxing bowel, promoting defecation and preparing intestinal tracts and treating intestinal tract-related operations (such as high-frequency electrocoagulation and/or high-frequency electrosection), and the arabinose can also effectively improve the side effects (such as nausea, vomit, abdominal distension and the like) of oral PEG, so that the arabinose and PEG combined drug has the advantages of excellent bowel clearing effect and good patient compliance.

2. In the composition, the L-arabinose tastes fresh and sweet, so that the composition is comfortable in taking, can avoid the feeling that the existing intestine clearing medicament PEG is difficult to swallow, greatly improves the compliance of patients, and improves the compliance of the intestine clearing and intestinal tract preparation of the patients.

Example 1

This example prepared an emulsion having the formulation shown in Table 1:

TABLE 1 formulation composition of the emulsion

The preparation method comprises the following steps:

the preparation method of the emulsion of the embodiment 1 of the invention is the same, and comprises the following steps:

(1) mixing the components of the water phase according to the prescription amount, heating to 70 ℃, and stirring and mixing to obtain a water-based phase A;

(2) mixing the oil phase components and the emulsifier components according to the prescription amount, heating to 70 ℃, and stirring and mixing to obtain an oily phase B;

(3) slowly injecting the aqueous phase A into the oily phase B under stirring, continuously and uniformly stirring for 6min, homogenizing for 5min at 12000 r/min by a homogenizer, and fully emulsifying to obtain the water-in-oil emulsion.

And (3) particle size performance measurement:

the average particle size of the emulsion measured by a Malvern laser particle sizer is 76.1 +/-8 nm.

Example 2

This example is similar to example 1, except that the emulsion formulation is shown in Table 2:

TABLE 2 prescription composition of the emulsion

Example 3

This example is similar to example 1, except that the emulsion formulation is shown in Table 3:

TABLE 3 prescription composition of the emulsion

Example 4

This example is similar to example 1, except that the emulsion formulation is shown in Table 4:

TABLE 4 prescription composition of the emulsion

Example 5

This example is similar to example 1, except that the emulsion formulation is shown in Table 5:

TABLE 5 prescription composition of the emulsion

Effect test 1

Examination of the Effect of the emulsions prepared in examples 1 to 5 on mouse excretion

Experimental methods

Experimental animals and their rearing: c57BL/6J mice, Specific Pathogen Free (SPF) grade, male, 6 weeks old; the common feed is D12450-B feed: 67.35 wt% carbohydrate, 19.2 wt% crude protein, 4.3 wt% fat. The temperature of the room is kept at 24-26 ℃ and the humidity is 40-60%.

Constructing a mouse constipation model: the mice are gavaged with loperamide suspension of 9mg/kg. body weight for 2 times/d, the first administration is doubled, and the constipation is established for 8 days continuously.

Experimental investigation:

constipation mice were randomly divided into model group, experimental group 1, experimental group 2, experimental group 3, experimental group 4 and experimental group 5, with 8 mice per group. In addition, 8 normal healthy non-constipated mice were randomly selected as a blank control group.

Mice in each group were fasted without water deprivation 12 before administration, and then mice in the blank control group, model group, experimental group 1, experimental group 2, experimental group 3, experimental group 4 and experimental group 5 were respectively gavaged with physiological saline, the emulsion prepared in example 1, the emulsion prepared in example 2, the emulsion prepared in example 3, the emulsion prepared in example 4 and the emulsion prepared in example 5, and after 0.5h, with ink containing montmorillonite powder (10mg/kg. BW), and each group of mice had normal drinking water. Starting from the ink filling, the first defecation time of each group of animals was recorded.

The administration pattern versus defecation time for the different groups of mice is shown in table 6:

TABLE 6 Effect of the administration of different groups of mice on defecation time (n-8)

Note: compared to the model group, "# is P < 0.05," # is P < 0.01.

As can be seen from Table 6, compared with the blank control group, the detection result of the first defecation time of the mice in the model group has significant difference (P < 0.01), which indicates that the constipation model of the mice is established. Compared with the model group mice, the defecation time of the experimental group 2-3 mice is shortened, which shows that the PEG4000 and the L-arabinose have the effects of promoting excretion and relaxing bowel. As can be seen from the data in experimental groups 1-5, the emulsion combination of PEG4000 and L-arabinose in combination has a synergistic effect on facilitating excretion and relaxing bowel compared to administration of PEG4000 or L-arabinose alone.

Effect test 2

Examination of the intestinal preparation of the emulsions prepared in examples 1 to 5

Evaluation criteria for intestinal tract preparation:

worthwhile scoring the gut readiness was scored in two parts. One is to score the colon into 3 segments (left half colon LC: rectum-sigmoid colon, mid-segment colon TC: transverse colon-descending colon, right half colon RC: ascending colon and cecum) and score the cleanliness of each segment. And secondly, scoring the liquid residual quantity in the whole colon. The worthwhile score ranks the intestinal cleanliness as 5 (0-4 points, respectively) in terms of cleanliness-worst. The best score of 0: the intestinal tract preparation condition is satisfied, the excrement residue in the intestinal cavity is absent, the retention of liquid dung is absent, the intestinal juice is very clear, the operation process is smooth and the mucous membrane observation is good; 1 is preferably: the intestinal tract preparation condition is satisfactory, the fecal residues in the intestinal cavity are a little, the fecal water is retained a little, flushing and suction are not needed, the mucous membrane observation is basically clear, and the operation can be smoothly carried out; 2, the classification is general: the preparation condition of the intestinal tract is not satisfactory, the excrement residue or the excrement block in the intestinal cavity is present, the mucous membrane is clear after the suction, and the operation is smooth; 3, poor: the preparation condition of the intestinal tract is not good, and although part of intestinal cavities are full of pasty excrement or liquid dung, mucous membranes can still be clearly seen through repeated flushing and suction; 4, the worst: the intestinal tract preparation is very poor, the intestinal cavity is filled with a large amount of pasty excrement or liquid dung, although the mucous membrane can not be clearly seen through repeated washing and suction, and the enteroscopy is not smooth. Scoring the amount of liquid in the Ottawa score scale, and scoring the amount of liquid in the whole colon (0-2 points for small, medium and large amounts, respectively). The final score of the gut cleansing ottawa score is the sum of the scores of the sections of the intestines and the liquid volume score, the lower the score, the better the intestinal tract preparation, and conversely, the higher the score, the worse the intestinal tract preparation. Scoring each intestinal segment by the Ottawa score scale to obtain a score of less than or equal to 2, and scoring the total score of less than or equal to 6 to obtain a qualified score; any section of the sausage is not qualified when the total score is more than 3 or more than 6. The high-quality (excellent) intestinal tract cleaning effect is that each intestinal section is less than or equal to 1 minute and the total score is less than 5 minutes.

The experimental method comprises the following steps:

250 cases of patients with pseudocolonoscopy have no pathological changes of important organs such as heart, liver, kidney and the like. The selected patients were randomly divided into experimental group 1, experimental group 2, experimental group 3, experimental group 4 and experimental group 5, each group had 50 persons, half of men and women, and the body weights and ages were substantially similar.

Dinner was taken a day prior to the examination on a low-residue/low-fiber diet, such as porridge alone or soup. The next 6h before examination, different emulsions are orally taken by different components respectively, the drinking water is minimum 1200ml, and the small mouth is closed if thirst happens. 4 hours before the examination, no water is drunk any more (only a small mouth is closed if thirst occurs). Fasting, proper ambulation, and excretion promotion on the day of examination until the examination is finished,

wherein the subjects of each group are administered as follows:

administration of experimental group 1: the emulsion prepared in example 1 was dosed as: 25g L-arabinose +50g polyethylene glycol 4000.

Administration of experimental group 2: the emulsion prepared in example 2 was dosed as: 50g of polyethylene glycol 4000.

Administration of experimental group 3: the emulsion prepared in example 3 was dosed as: 25g L-arabinose.

Administration of experimental group 4: example 4 the emulsion was prepared at the following dosages: 25g L-arabinose +50g polyethylene glycol 4000.

Administration of experimental group 5: the emulsion prepared in example 5 was dosed as: 25g L-arabinose +50g polyethylene glycol 4000.

The results of the bowel preparation are shown in table 7:

TABLE 7 comparison of bowel preparation quality

As can be seen from table 7, the emulsion containing L-arabinose and polyethylene glycol 4000 significantly enhanced the effect of intestinal tract preparation compared to the administration of L-arabinose or polyethylene glycol emulsion alone, indicating that the combination of L-arabinose and PEG4000 had a synergistic effect in intestinal tract preparation.

When PEG4000 is used for preparing intestinal tracts, patients often have side effects such as nausea, vomiting and abdominal distension, and the nausea, vomiting and abdominal distension of experimenters are observed simultaneously in the process of preparing the intestinal tracts, and the observation results are shown in a table 8:

TABLE 8 side effects during preparation of the intestine

As can be seen from Table 8, compared with the PEG4000 emulsion alone, after the PEG4000 and the L-arabinose are combined, the arabinose can remarkably reduce the side effects of the PEG4000 such as nausea, vomiting and abdominal distension, so that the L-arabinose can improve the compliance of patients to oral administration of the PEG 4000. Furthermore, from the experimental results of the groups of examples 1, 4 and 5, it can be seen that in the oil phase, the combination of sunflower oil and olive oil can significantly reduce the side effects of PEG4000, such as nausea, vomiting and abdominal distension, compared to the individual sunflower oil or olive oil. Thus, the experimental results of table 8 show that the emulsion of example 1 has excellent compliance.

The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. An excretion promoting composition, wherein the active components of the composition consist of PEG4000 and L-arabinose;

the weight ratio of the PEG4000 to the L-arabinose is 1-3: 1.

2. The composition of claim 1, wherein the composition is a pharmaceutical composition, a food composition, or a nutraceutical composition.

3. The composition of claim 1, wherein the composition is in the form of an emulsion, a tablet, a capsule, an oral liquid, a granule, a powder, or a syrup.

4. The composition of claim 1, wherein the composition is an emulsion comprising:

(A) an aqueous phase comprising L-arabinose, PEG4000 and water;

(B) the oil phase comprises rapeseed oil, sunflower seed oil and olive oil; and

(C) and the emulsifier comprises sorbitan monooleate and glyceryl monostearate.

5. Use of a composition according to claim 1 for the preparation of a medicament for one or more uses selected from the group consisting of: (a) as a laxative; (b) for bowel preparation.